Vaccine-Induced Thrombotic Thrombocytopenia Following Coronavirus Vaccine: A Narrative Review

Abstract

The novel coronavirus pandemic has taken a toll on the global healthcare systems and economy. Safety precautions, along with vaccination, are the most effective preventive measures. The global vaccination program against COVID-19 has dramatically reduced the number of deaths and cases. However, the incidence of thrombotic events and thrombocytopenia post-COVID-19 vaccination known as vaccine-induced thrombotic thrombocytopenia has raised safety concerns. This has led to an element of vaccine hesitancy. The exact mechanism for vaccine-induced thrombotic thrombocytopenia is unknown. Although the incidence of thrombosis associated with COVID-19 vaccination is low, it still requires attention, especially in older people, smokers, and people with preexisting comorbidities. This study aims to review the pathophysiology, diagnosis, and management of vaccine-induced thrombotic thrombocytopenia, to provide a concise and comprehensive update.

Full text

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Vaccine-induced thrombotic thrombocytopenia following coronavirus vaccine: A
narrative review
Syed Hassan Ahmed, Taha Gul Shaikh, Summaiyya Waseem, Nashwa Abdul Qadir,
Zohaib Yousaf, Irfan Ullah
PII: S2049-0801(21)00938-9
DOI: https://doi.org/10.1016/j.amsu.2021.102988
Reference: AMSU 102988
To appear in: Annals of Medicine and Surgery
Received Date: 5 September 2021
Revised Date: 27 October 2021
Accepted Date: 28 October 2021
Please cite this article as: Ahmed SH, Shaikh TG, Waseem S, Qadir NA, Yousaf Z, Ullah I, Vaccine-
induced thrombotic thrombocytopenia following coronavirus vaccine: A narrative review, Annals of
Medicine and Surgery (2021), doi: https://doi.org/10.1016/j.amsu.2021.102988.
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Vaccine-Induced Thrombotic Thrombocytopenia Following Coronavirus Vaccine: A Narrative Review
Syed Hassan Ahmed1, Taha Gul Shaikh1, Summaiyya Waseem1, Nashwa Abdul Qadir1, Zohaib Yousaf2,
Irfan Ullah3
1Dow University of Health Sciences, Karachi, Pakistan
2Department of Internal Medicine, Hamad Medical Corporation, Doha, Qatar
3Kabir Medical College, Gandhara University, Peshawar, Pakistan
Corresponding Author
Zohaib Yousaf (MBBS, MSc, FACP)
Department of Internal Medicine,
Hamad Medical Corporation, Doha, Qatar
Email: zohaib.yousaf@gmail.com
Irfan Ullah, MBBS
Kabir Medical College Gandhara University, Peshawar, 25000 Pakistan
Email: irfanullahecp2@gmail.com
Abstract= 121
Word Count= 2244
Tables and figure= 1 Table and 2 Figures
References= 65
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Vaccine-Induced Thrombotic Thrombocytopenia Following Coronavirus Vaccine: A
Narrative Review
Abstract
The novel coronavirus pandemic has taken a toll on the global healthcare systems and
economy. Safety precautions, along with vaccination, are the most effective preventive
measures. The global vaccination program against COVID-19 has dramatically reduced the
number of deaths and cases. However, the incidence of thrombotic events and
thrombocytopenia post-COVID-19 vaccination known as vaccine-induced thrombotic
thrombocytopenia has raised safety concerns. This has led to an element of vaccine
hesitancy. The exact mechanism for vaccine-induced thrombotic thrombocytopenia is
unknown. Although the incidence of thrombosis associated with COVID-19 vaccination is low,
it still requires attention, especially in older people, smokers, and people with preexisting
comorbidities. This study aims to review the pathophysiology, diagnosis, and management of
vaccine-induced thrombotic thrombocytopenia, to provide a concise and comprehensive
update.
Key words: COVID-19, COVID-19 Vaccine, Vaccine Induced Thrombotic Thrombocytopenia,
Vaccine Induced Immune Thrombotic Thrombocytopenia, Thrombotic thrombocytopenia,
VITT
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Introduction
The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) cases were initially
reported in Wuhan, China, towards the end of 2019. Following its extensive spread, the
World Health Organization (WHO) declared COVID-19 a pandemic in March 2020. [1] To the
date, April 16, approximately 207 million confirmed cases have been reported, and 4.3
million deaths [2].
Coordinated global efforts led to the development of COVID-19 vaccines, followed by
emergency use authorization within nine months of the pandemic [3]. These vaccines are
now widely available for public administration [4]. The vaccines are safe and effective in
preventing severe infection, hospitalization, and death [5,6]. To date, 4.4 billion vaccine doses
have been administered [2]. The common adverse effects following COVID-19 vaccination are
injection site pain and transient, self-limited systemic symptoms like headache, fever,
myalgias, etc. [7].
Recently, a more severe adverse effect, thrombocytopenia with or without thrombosis, has
been reported following SARS-CoV-2 vaccination. Thrombocytopenia is a medical condition
characterized by platelets lower than 150,000/microliter and is associated with a risk of
bleeding and thrombosis [8]. Such reports have raised concerns over the safety profile and
hesitancy towards the available vaccines [9]. The term "Vaccine-Induced Thrombotic
Thrombocytopenia" describes post-vaccination thrombocytopenia cases. VITT is
characterized by thrombosis at unusual sites and thrombocytopenia following vaccination [9].
While VITT has been associated with both mRNA and viral vector vaccines, its prevalence is
higher in viral vectored vaccines [7]. Following the incidence of 30 thromboembolism cases in
March 2021, Oxford/AstraZeneca (AZD1222) was transiently suspended in numerous
European countries [10]. Later the pharmacovigilance risk assessment committee (PRAC) of
the European medical agency (EMA) reviewed all cases and declared thrombosis and
thrombocytopenia as rare adverse effects of AZD1222. However, based on risk-benefit
assessment, the vaccine was later declared safe for use [11]. Owing to a similar reason, in
April 2021, Johnson & Johnson’s Janssen (Ad26.CoV2.S) administration was also temporarily
suspended [12].
Herein, we review the association between SARS-CoV-2 vaccines and VITT. This review
evaluates the potential pathophysiology and clinical approach to diagnoses and management
of VITT.
Literature Review
The work has been reported in line with the PRISMA 2020 criteria [13]. Two authors
(SHA, SW) dependently conducted a thorough literature search over PubMed and
Clinicaltrials.gov from inception till August 16, 2021, without any language
restriction. To achieve comprehensive results, search string comprised of keywords,
"SARS-CoV-2 Vaccine", "Coronavirus Vaccine," "Corona Vaccine," "COVID-19
Vaccine", "thrombotic thrombocytopenic," "Vaccine-Induced Thrombotic
Thrombocytopenia," "VITT," "thrombocytopenia," "reduced platelet count," using
BOOLEAN operators. Synonyms, related terms, and spelling variants were also
engaged. All relevant case reports, case series, cohort studies, editorials, and
correspondences were reviewed. Any discrepancies were resolved via discussion with
a third reviewer (IU). The results of the literature search are shown in figure 1.
Following studies selection, two independent authors (TGS, NAQ) extracted all the
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relevant data into a table comprising of author's name, patient's age, and sex, past
medical history, presenting complaint, laboratory findings, radiological findings,
treatment interventions, and outcome. Any discrepancies were resolved by discussion
with a third reviewer (IU). All significant findings are summarized in table 1.
Figure 1: PRISMA Flowchart
Demographics
The retrieved studies comprise data of 44 patients (32 females, 11 males, 1 not defined) with
a mean age of 44.9 ± 14.3 years. The following figure (Figure 2) depicts the geographical
distribution of the reported cases around the globe, with the majority of cases arising in
Europe. Based on these and future reporting, we can predict the potential spatial spread,
geographical locations that may be more susceptible than others and this may help us
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establish links between different genetic and environmental factors, predisposing an
individual to such consequences of vaccines.
Figure 2: Geographical Distribution of the Reported Cases
Pathophysiology
The exact pathophysiology behind VITT is unclear. As shown in Table 1, most of the cases
presented with thrombocytopenia, elevated D-dimer, and positive titers of IgG antibodies
against platelet factor 4 (PF-4)[14–22]. Based on these findings, this syndrome is closely
related to heparin-induced thrombocytopenia (HIT), a medical condition characterized by
thrombocytopenia, and the presence of antibodies against the Heparin-PF4 complex [23].
HIT, an autoimmune reaction to heparin, involves the generation of IgG antibodies against
the Heparin-PF4 complex. The Fc portion of these antibodies adheres to the complex, binds
to the FcYRIIa receptors [24], and initiates platelets activation via intracellular signaling
involving spleen tyrosine kinase [25]. This results in the release of microparticles and a
procoagulant state [26,27]. Furthermore, clearance of activated and antibody-bound
platelets by the reticuloendothelial system culminates in thrombocytopenia [28]. A
prerequisite in the diagnosis of HIT includes a known recent exposure to heparin. A condition
labeled "Autoimmune Heparin-Induced Thrombocytopenia (aHIT)” manifests with clinical and
laboratory findings without any prior use of heparin [29]. Based on this resemblance, a
comparison has been drawn between VITT and variants of aHIT [30], and hence, we may
assume that a similar mechanism follows post-vaccination. However, the mechanism behind
the generation of these antibodies is yet to be elucidated.
In HIT, the electrostatic interaction between positively charged PF4 and negatively charged
heparin culminates in the formation of the Heparin-PF4 complex [31]. This phenomenon has
also been observed with other negatively charged molecules like numerous polyphosphates
[32], Polyvinyl phosphonate [33], nucleic acids [34], etc. According to Visentin et al. [33],
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numerous negatively charged molecules, spaced about 0.5 nm apart along the molecular
backbone and of sufficient length, can form complexes with PF4 while being detectable by
the antibodies. Hence, components of vaccines can be expected to play a crucial role in the
generation of PF4-polyanions complex and antibodies against them. Moreover,
environmental factors and genetic predisposition can exacerbate clinical presentation. For
example, specific genotypes encoding FcRIIA have been associated with an increased risk of
thrombosis in individuals with anti-PF4-polyanion antibodies [24].
Another postulated mechanism involves cross-reactivity of anti-SARS-CoV-2 spike protein
antibodies that generates following SARS-CoV-2 vaccination with PF4. This may be
attributable to molecular mimicry, a phenomenon whereby a certain degree of resemblance
exists between the pathogens and the host's antigens [35]. Kanduc et al. [36] report massive
homogeneity between the SARS-CoV-2 spike glycoprotein and human proteins, thus further
strengthening this hypothesis. This structural resemblance can also explain the findings of
thrombocytopenia [37] and anti-PF4 antibodies [38] in certain SARS-CoV-2 patients. However,
the currently available literature suggests no evidence of cross-reactivity [38,39].
Zhang et al. [40] investigated the findings of thrombosis and thrombocytopenia in SARS-CoV-
2 patients. They reported spike protein's ability to stimulate platelet activation and thrombus
formation via the Mitogen-activated protein kinase (MAPK) pathway. Based on the findings
[40], the generation of spike protein following vaccination can also play a pivotal role in
inducing thrombocytopenia and thrombosis via spike protein-ACE2 interaction-induced
platelets activation. However, it remains unanswered if similar interactions can be observed
post-vaccination with vector or mRNA vaccines. Moreover, some evidence [41] reveals
potential interactions between adenovirus particles and circulating platelets leading to
platelet activation and aggregation. The possibility of such interactions in the case of viral
vector-based vaccines cannot be ruled out and requires further investigation. Furthermore,
as shown in table 1, the findings of negative anti-PF4 antibodies in selective cases indicate
involvement of a non-HIT like mechanism hence strengthening the above suggested
hypothesis.
Future research should focus on potential interactions between spike proteins and platelets
and the phenomenon of cross-reactivity. Another intriguing aspect of the higher prevalence
of VITT among individuals vaccinated with viral vector-based vaccines needs to be
investigated in the search for potential links. Development of thrombosis in selective
individuals and incidence of rare site thrombosis like cerebral venous sinuses deserve equal
attention for the exact pathophysiology to be elucidated. Lastly, the development of anti-PF4
antibodies only in certain VITT patients can also provide important clues in determining the
pathogenesis.
Diagnosis
Following the escalation in reported thrombocytopenia and thrombosis cases post COVID-19
vaccination, the American Society of Hematology (ASH) reviewed all the reported cases and
laid specific ground rules to diagnose this novel presentation. As per the ASH [42], cases
meeting the following criteria can be identified as VITT:
a) Symptom onset 4 to 42 days post SARS-CoV-2 vaccination
b) Any venous or arterial thrombosis (often cerebral or abdominal)
c) Thrombocytopenia
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d) Antibodies to platelet factor 4 (PF4) identified by enzyme-linked immunosorbent test
(ELISA)
e) Markedly elevated D-dimer (> 4 times upper limit of normal)
Individuals presenting with the complaints of severe headache, visual changes, abdominal
pain, nausea, vomiting, back pain, shortness of breath, leg pain or swelling, petechiae, easy
bruising, or bleeding, 4 to 42 days post-vaccination, must be evaluated critically for the
condition mentioned above. Laboratory investigations, including CBC with platelet count, PF4
ELISA, d-dimer, fibrinogen, and imaging techniques for thrombosis, can play a crucial role in
timely diagnosis and management. [42]
Management
Currently, numerous potential pharmacological therapies are being evaluated in the line of
management for VITT. The outcomes range from being propitious to contraindicated or
variable in different individuals. Briefed below are specific interventions being employed to
overcome VITT.
Intravenous Immunoglobulins (IVIG)
The currently available evidence acknowledges IVIG as a potential treatment depicting
remarkable success. Hence it is now incorporated into the treatment regimen. A potential
explanation for this involves the Fcγ receptor blockade by the antibodies. The recommended
dose in VITT is 1-2g/kg of the person's body weight. However, ideally, the administered IVIG
should be the ones collected before the pandemic. The plausible explanation being vaccine
response deterioration due to COVID-19 antibodies present in the donated IGs [43].
Anticoagulants
There has been growing evidence of their efficacy in patients with VITT [44]. In some
instances, preliminary trials to validate its effectiveness and progressive clinical worsening in
some instances [45] have raised suspicions over its use regarding heparin. Therefore, the
American society of hematology (ASH) suggests avoiding the use of heparin unless VITT has
been ruled out or another condition diagnosed [42]
The drug of choice is direct oral anticoagulants (dabigatran, apixaban, rivaroxaban, edoxaban,
and fondaparinux) or parenteral direct thrombin inhibitors (e.g., bivalirudin and argatroban).
The absolute contraindication following anti-coagulation therapy includes a high risk of
bleeding. Hence strict clinical monitoring is crucial after initiating oral anticoagulants.
Steroids
Most cases of VITT described steroids as a clinically effective treatment option. However,
further data is needed to move past the anecdotal evidence. The above data and prediction
are based on their successfully reported usage in our included cases and recently, by Schultz
et al. [46], where the combined IVIG and steroids were supported.
Platelet Infusion
This therapy is only indicated in significant bleeding. Goel et al. [47] reported a five times
increase in mortality of patients infused with platelets following thrombocytopenia. In our
included studies, eight reportedly administered platelet infusion. Following Goel et al.
[47,48], only two patients survived [49].
Platelet Exchange
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Plasma exchange was used in three cases. Two out of the three patients survived [50][51].
Relevant details by Garnier et al. were unavailable [14]. Plasma exchange is used in refractory
VITT [52]. Clinically, there is insufficient data to evaluate whether plasma exchange can be
administered safely in VITT.
Plasma exchange is not a standard treatment option in HIT [42]. Extrapolating this to VITT, we
may assume similar effects on patients with VITT. However, more data is required to draw
any conclusion.
Aspirin and Rituximab
Aspirin or other anti-platelets are currently contra-indicated in VITT due to increased risk of
bleeding. Smith et al. [53] suggested a possible prophylactic role of antiplatelets in VITT. This
highlights the need for more work in this area.
Rituximab is not recommended currently due to its longer response time (6-8 weeks) [42].
Moreover, this drug’s mechanism of action can be explained via its downregulation of CD-20
B-cells. This can potentially lead to the inactivation of antibodies against COVID-19, hence
rendering the vaccine administration useless.
Treatment Regimen
The following regimen is per the American Society of Hematology (ASH) [42], International
Society on Thrombosis and Haemostasis (ISTH) [54], and National Institute for Health and
Care Excellence (NICE) in the United Kingdom:
1. Start IVIG.
2. The ISTH guidelines recommend administering steroids if a patient's platelet count is
less than 50 x 109/L.
3. Platelet infusion and plasma exchange should not be considered initially.
4. Based on their history and previous clinical profile, patients shall be started an
anticoagulant (non-heparin). Vitamin K antagonists should be avoided while the
platelet count is low. Moreover, direct thrombin inhibitors should be avoided in
pregnant women. DOACs and fondaparinux are suitable for noncritically ill patients.
5. For patients having less than 50 ×103/μL and severe risk of bleeding, IV direct
thrombin inhibitors can be used. This will lead to a shorter half-life and rapid action.
6. Fibrinogen levels should be strictly monitored and kept in range (>1.5 g/L.)
7. If platelet count remains less than 30 x 109/L despite intravenous immunoglobulin
and steroid treatment or fibrinogen level is less than 1 g/L, plasma exchange can be
considered after an opinion with hematologists.
Conclusion
VITT is a rare adverse effect of SARS-CoV-2 vaccination, and the benefits of COVID-19
vaccines continue to outweigh the rare side effects. However, while its incidence is low, there
is undoubted an overwhelming need to discern the precise pathophysiology behind this
syndrome to establish proper management protocols. Questions like why certain coronavirus
vaccines carry a higher risk than others, why specific individuals develop thrombosis while
others don’t, higher prevalence in a particular gender and age group, and the impact of
different interventions in such patients need to be investigated before a clear conclusion can
be drawn. Lastly, future studies must take into consideration both pre-and post-vaccination
investigations to discern the role of any underlying condition.
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Acknowledgments
None
Ethics statement
Not applicable
Funding
None
Conflict of interests
The authors declare that there is no conflict of interests
Provenance and peer review
Not commissioned, externally peer-reviewed
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Journal Pre-proof

Author
Sex and
Age
Past Medical
history
Presenting
Complaint
Vaccine
administered
Laboratory
findings
Radiological findings
Intervention
Outcome
Al Maqbali et al.
[55]
59 y/o
Female
Type 2 diabetes
mellitus,
osteoarthritis, and
COVID-19
pneumonia in
September 2020,
OCP
Sudden onset left
leg pain 7 days
after receiving
her first dose.
Pfizer-
BioNTech
mRNA
Platelet= 182 x
109/L
D-dimer= 24
mg/L
Bifurcation of the pulmonary
trunk and main pulmonary
arteries emboli extending to
the lobar segmental and
subsegmental branches
Rivaroxaban 2 x 15 mg daily
for 21 days, followed by
rivaroxaban 20 mg daily for a
total of 3 months
Recovered
Muir et al. [56]
48 y/o
Male
N/A
3 days history of
malaise and
abdominal pain
Ad26.COV2. S
vaccine
(Johnson &
Johnson/Janss
en)
Platelet=13,000/
mm3
D-dimer=117.5
mg/liter
Cerebral venous sinus
thrombosis involving the right
transverse and straight
sinuses and extensive
splanchnic vein thrombosis
Argatroban &
IVIG at a dose of 1g/kg of
ideal body weight
Critically ill
at the time
of the
report
Sheikh et al. [57]
50 y/o
Male
N/A
Headache,
vertigo, and vision
changes
ChAdOx1
nCoV-19
(AstraZeneca)
N/A
Central venous sinus
thrombosis (CVST) in
transverse and sigmoid
sinuses
Desirudin, IVIG at 1g/kg/hour
and Prednisolone at 1mg/kg
daily
Recovered
Ramdeny et al.
[58]
54 y/o
Male
Rare congenital limb
malformation
7-day history of
worsening
headache,
bruising and
unilateral right
calf swelling
ChAdOx1
nCoV-19
(AstraZeneca)
Platelet= 34. x
109 /L
D-dimer= 6000
ng/ml
Extensive cerebral venous
sinus thrombosis
Therapeutic IVIG and
anticoagulation
Recovered
Bano et al. [49]
53 y/o
Female
N/A
Worsening
headache and
weakness of the
right arm and leg
ChAdOx1
nCoV-19
(AstraZeneca)
Platelet=
24×10⁹/L
D-dimer=5620
ng/ml
Cerebral Venous sinus
thrombosis
Three units of platelets were
transfused before urgent
neurosurgical intervention
Death
Bano et al. [49]
61 y/o
Female
N/A
3-day history of
progressive
dyspnea, pain,
and swelling in
ChAdOx1
nCoV-19
(AstraZeneca)
Platelet=
25×10⁹/L
D-dimer =
9376 ng/mL
Bilateral PE with right heart
strain
One unit of platelets, LMWH,
was given twice. After which,
anticoagulation was switched
to treatment dose
Recovered
Journal Pre-proof

the right leg
fondaparinux. Further platelet
transfusion was withheld. The
patient was treated with IVIG
1 g/kg single dose and pulsed
dexamethasone 20 mg once
daily for 4 days
Wiedmann et al.
[59]
42 y/o
Female
N/A
Severe
headaches,
nausea, vomiting,
fluctuating level
of consciousness,
and right-sided
hemiparesis
ChAdOx1
nCoV-19
(AstraZeneca)
N/A
Left transverse sinus and
sigmoid sinus
cerebral sinus vein thrombosis
(CSVT) and cortical vein
thrombosis
IV methylprednisolone (1
mg/kg) daily and IVIG (1 g/kg)
for 2 days
Death
Wiedmann et al.
[59]
37 y/o
Female
N/A
2-day history of
headaches, fever,
transient
numbness in the
right foot, and
right-sided visual
disturbance
ChAdOx1
nCoV-19
(AstraZeneca)
N/A
CSVT in the left transverse
and sigmoid sinus and left
occipital CSVT
Urgent suboccipital
craniectomy was performed
and cerebellar herniation
encountered during surgery
Death
Wiedmann et al.
[59]
39 y/o
Female
N/A
Abdominal pain
and headaches
ChAdOx1
nCoV-19
(AstraZeneca)
Platelet= 119 ×
109/L
Small cerebellar hemorrhage.
CSVT in the inferior sagittal
sinus, vein of Galen and
straight, right transverse and
sigmoid sinuses. Bilateral
segmental pulmonary emboli,
thrombosis in uterine veins.
IVIG, steroids, warfarin
Recovered
Wiedmann et al.
[59]
54 y/o
female
N/A
Numbness of left-
sided limbs 6 days
post-vaccination,
left-sided
paralysis and
facial nerve palsy.
ChAdOx1
nCoV-19
(AstraZeneca)
N/A
CSVT in nearly all major
venous sinuses
Methylprednisolone (1 mg/kg)
and IVIG (1 g/kg) for 2 days
and decompressive
hemicraniectomy
Death
Ruhe et al. [51]
84 y/o
Female
N/A
Partial
hemiplegia,
Pfizer-
BioNTech
Platelet count=
45 × 109/L
Multiple subacute emboli
without vessel occlusion.
Corticosteroid and plasma
exchange therapy (PEX) with
fresh frozen plasma.
Recovering
Journal Pre-proof

scattered
petechiae, and
severe arterial
hypertension.
mRNA
Rituximab at day 2 as second
corticosteroid
Gesseler et al.
[60]
47 y/o
Female
N/A
Progressive
headache 7 days
after the first
dose
ChAdOx1
nCoV-19
(AstraZeneca)
Platelet= 9 x
109/L
D-dimer >35.2
mg/L
Large-scale sinus thrombosis
IVIg at 1g/kg, Argatroban and
corticosteroids. Platelet
therapy was administered
before the decompressive
surgery. During operation,
artificial hemostyptics and
transfusions were done.
Death
Gesseler et al
[60]
50 y/o
Female
N/A
Progressive
headache 10 days
after first dose
ChAdOx1
nCoV-19
(AstraZeneca)
Platelet= 24 x
109/L
D-dimer >35.2
mg/L
Large-scale sinus thrombosis
IVIg at 1g/kg, Argatroban and
corticosteroids. Platelet
therapy was administered
before the decompressive
surgery. During operation,
artificial hemostyptics and
transfusions were done.
Death
Gesseler et al.
[60]
44 y/o
Female
N/A
Progressive
headache 12 days
after the first
dose
Ad26.COV2. S
vaccine
(Johnson &
Johnson/Janss
en)
Platelet= 48 x
109/L
D-dimer
>35.2mg/L
Large-scale sinus thrombosis
IVIg at 1g/kg, Argatroban and
corticosteroids. Platelet
therapy was administered
before the decompressive
surgery. During operation,
artificial hemostyptics and
transfusions were done.
Death
Patel et al. [15]
33 y/o Male
N/A
Back pain,
hematuria,
headache, and
right lower leg
pain for 1 week
ChAdOx1
nCoV-19
(AstraZeneca)
D-dimer >20
mg/L
Anti-PF4
antibodies were
positive
PE in left pulmonary artery
IV Argatroban, IVIG, and
warfarin
Recovered
Patel et al. [15]
28 y/o Male
N/A
Back pain and
lower limb
weakness
ChAdOx1
nCoV-19
(AstraZeneca)
Elevated D-
dimers and
positive anti-PF4
antibodies
Bilateral PEs and left proximal
DVT
IV Argatroban, IVIG, and
warfarin
Recovered
Journal Pre-proof

Patel et al. [15]
61 y/o Male
N/A
Exertional
dyspnea and
pleuritic chest
pain
ChAdOx1
nCoV-19
(AstraZeneca)
Elevated D-
dimers and
positive anti-PF4
antibodies
Bilateral PEs
IV Argatroban, IVIG, and
warfarin
Recovered
Suresh et al. [17]
27 y/o Male
N/A
Intermittent
headaches
associated with
eye floaters
ChAdOx1
nCoV-19
(AstraZeneca)
Platelets= 12 x
109/L
Anti-P4
antibodies were
positive
Cerebral venous sinus
thrombosis.
IVIg (1g/kg) once a day,
Dabigatran, Idarucizumab,
Prednisolone once daily
(1mg/kg) with proton pump
inhibitors cover
Death
Mehta et al. [16]
32 y/o Male
N/A
Thunderclap
headache,
subsequent left-
sided
incoordination,
and hemiparesis
ChAdOx1
vaccine
(AZD1222,
Vaxzevria)
Platelets= 30 x
109 /L
Superior sagittal sinus and
cortical vein thrombosis
No treatment since the
condition continued to
deteriorate
Death
Mehta et al. [16]
25 y/o Male
Primary sclerosing
cholangitis and
migraines
Photophobia,
neck stiffness,
visual
disturbances,
petechial rashes,
and gum bleeding
ChAdOx1
vaccine
(AZD1222,
Vaxzevria)
Platelets= 19 x
109 /L
Positive anti-P4
antibodies
Superior sagittal sinus
thrombosis with cortical veins
involvement.
Intravenous unfractionated
heparin, platelet transfusions,
IV dexamethasone, IVIG, and
intravenous levetiracetam
Death
Xie et al. [50]
23 y/o
N/A
Chest pain and
breathlessness
N/A
Platelets= 73 X
109 /L
D-dimer= 17548
µg/L
Pulmonary emboli, right
ventricle thrombus, and
splenic vein thrombus
Apixaban, intubation,
ventilation, plasma exchange,
IV methylprednisolone, and
heparin infusion
Recovered
Sørensen et al.
[22]
33 y/o
Female
Migraine
Headache and
general malaise
ChAdOx1
nCoV-19
(AstraZeneca)
Platelets= 51 X
109 /L
Anti-PF4
antibodies were
positive
Cerebral venous sinus
thrombosis and portal vein
thrombosis
Tinzaparin, Fondaparinux
Recovered
Dias et al. [61]
47 y/o
Female
Iron deficiency
anemia due to
adenomyosis
Headache,
nausea, and
photophobia
Pfizer-
BioNTech
mRNA
Platelets=
34000/mL
Anti-PF4
antibodies were
negative
Thrombosis of superior
sagittal, right lateral,
transverse, sigmoid sinuses
and jugular vein and left
sigmoid sinus
Acetazolamide, enoxaparin
60mg, and warfarin
Recovered
Journal Pre-proof

Dias et al. [61]
67 y/o
Female
Multiple cerebral
cavernous
malformations,
hypertension,
diabetes,
dyslipidemia, viral
myocarditis, and
depression
Right lower limb
clonic
movements,
motor deficit, loss
of consciousness,
and headache
Pfizer-
BioNTech
mRNA
Platelets=
164000/mL Anti-
PF4 antibodies
were negative
Thrombosis of high convexity
cortical veins, superior
sagittal, right transverse, and
sigmoid sinus and jugular vein
Levetiracetam 500 mg,
enoxaparin 80 mg, dabigatran
150 mg
Recovered
Tiede et al. [18]
63 y/o
Female
N/A
Headache,
somnolence,
dysphasia, right-
sided
hemiparesis, and
arterial
hypertension
ChAdOx1
vaccine
(AZD1222,
Vaxzevria)
Platelets= 27/ nl
D-dimer >35.2
mg/L
Anti-PF4
antibodies were
positive
Left transverse and sigmoid
sinus thrombosis, cerebral
venous sinus thrombosis
Heparin and eculizumab
Recovering
Tiede et al. [18]
67 y/o
Female
N/A
Headache
ChAdOx1
vaccine
(AZD1222,
Vaxzevria)
Platelets= 40/ nl
D-dimer >35.2
mg/L
Anti-PF4
antibodies were
positive
Aortic arch thrombi and
cerebral arterial embolism
Argatroban and IVIG
Recovered
Tiede et al. [18]
61 y/o
Female
N/A
Fatigue
ChAdOx1
vaccine
(AZD1222,
Vaxzevria)
Platelets= 12/ nl
D-dimer >35.2
mg/L
Anti-PF4
antibodies were
positive
Splanchnic vein thrombosis
Argatroban, IVIG, alteplase,
eculizumab
Recovering
Tiede et al. [18]
61 y/o
Female
N/A
Headache,
dysarthria, left-
sided hemiplegia,
conjugated gaze
palsy
ChAdOx1
vaccine
(AZD1222,
Vaxzevria)
Platelets= 62/nl
D-dimer> 35.2
mg/L
Anti-PF4
antibodies were
positive
Right internal carotid and
middle cerebral artery (M1)
thrombosis and cerebral
arterial thrombosis
Argatroban and IVIG
Recovering
Journal Pre-proof

Guetl et al. [62]
50 y/o
Female
N/A
Severe headache
and severe back
pain
ChAdOx1
nCoV-19
(AstraZeneca)
Platelets=
27 × 109 /L
D-dimer >33
mg/L
Anti-PF4
antibodies were
negative
Multifocal thrombus in the
pelvic region and embolus in
the posterior–basal right
lower lobe
IVIG, dexamethasone 40mg,
argatroban, and dabigatran
Recovered
Schultz et al. [46]
37 y/o
Female
Pollen allergy
Headaches, fever,
and visual
disturbance
ChAdOx1
nCoV-19
(AstraZeneca)
Platelets= 22000
mm3
D-dimer> 35
mg/L
Thrombosis in the left
transverse, left sigmoid
sinuses, and cortical veins
Dalteparin, platelets, and
decompressive craniotomy
Death
Schultz et al. [46]
42 y/o
Female
Pollen allergy
Headache and
drowsiness
ChAdOx1
nCoV-19
(AstraZeneca)
Platelets= 14000
mm3
Thrombosis in the left
transverse left sigmoid
sinuses and cortical veins
Dalteparin, platelet
transfusion, IVIg 1g/kg,
methylprednisolone 1mg/kg,
and hemicraniectomy
Death
Schultz et al. [46]
32 y/o Male
Asthma
Back pain
ChAdOx1
nCoV-19
(AstraZeneca)
Platelets= 10,000
mm3
Thrombosis of portal vein
branches
IVIg 1g/kg, prednisolone
1mg/kg, dalteparin
Recovered
Schultz et al. [46]
39 y/o
Female
N/A
Headache and
abdominal pain
ChAdOx1
nCoV-19
(AstraZeneca)
Platelets= 70000
mm3
Thrombosis of Inferior sagittal
sinus, straight sinus, the vein
of Galen, right transverse
sinus, and right sigmoid sinus
IVIg 1g/kg, prednisolone
1mg/kg, dalteparin, warfarin
Recovered
Schultz et al. [46]
54 y/o
Female
Hypertension
Headache and
hemiparesis
ChAdOx1
nCoV-19
(AstraZeneca)
Platelets= 19000
mm3
Thrombosis of the cortical
vein, superior sagittal vein,
both transverse sinus and left
sigmoid sinus
IVIg 1g/kg,
methylprednisolone 1mg/kg
Death
Malik et al. [63]
43 y/o
Female
Hyperlipidemia,
anxiety, depression,
obesity, obstructive
sleep apnea, and
gastroesophageal
Headache, fever,
body aches, chills,
mild dyspnea, and
light-headedness
Ad26.COV2. S
vaccine
(Johnson &
Johnson/Janss
en)
Platelets=
27 × 109 /L
D-dimer= 35.2
mg/L
Anti-PF4
Pulmonary Embolism and
Intracerebral thrombus
IVIg, fondaparinux, fioricet
and topiramate
Recovered
Journal Pre-proof

disease
antibodies were
positive
Garnier et al. [14]
26 y/o
Female
N/A
Nausea and
headache
ChAdOx1
nCoV-19
(AstraZeneca)
Anti-PF4
antibodies were
positive
Occlusion in middle cerebral
artery
Corticosteroids,
anticoagulants, and plasma
exchange
N/A
Abadi et al. [20]
30 y/o
Female
N/A
Headache, neck
pain, lower
extremity pain,
and weakness
Ad26.COV2. S
vaccine
(Johnson &
Johnson/Janss
en)
Platelets= 80 x
103 / µL
Anti-PF4
antibodies were
positive
Acute deep vein thrombosis
involving posterior tibialis and
popliteal veins, obstructive
thrombosis in right transverse
sinus extending to right
sigmoid sinus and jugular
bulb, pulmonary embolism
Argatroban and Bivalirudin
Recovered
Agostino et al.
[64]
54 y/o
Female
N/A
Acute
cerebrovascular
accident
ChAdOx1
nCoV-19
(AstraZeneca)
Normal D-dimer
Deep vein thrombosis, acute
basilar thrombosis
N/A
Death
Mauriello et al.
[65]
48 y/o
Female
Penicillin allergy,
episode of
thrombocytopenia in
2016.
Postmortem analysis
indicated pre-
existing
thrombocytopenia
Progressive
headache, back
pain, moderate
right lower limb
pain, and
disseminated
ecchymosis that
required
hospitalization on
day 18
ChAdOx1
nCOV-19
AstraZeneca
Platelets=
32000/μL
D-dimer=
10mg/mL
Thrombo-embolic filling
defects affecting the
pulmonary artery, sigmoid
transverse sinus thrombosis,
right internal jugular vein
thrombosis, right temporo-
occipital intraparenchymal
hemorrhage
Initially low molecular weight
heparin, anti-hypertensive,
oral double (dabigatran 110
mg/die + rivaroxaban 30
mg/die) anticoagulants, IV
methylprednisolone,
dabigatran antagonist, and a
decompressive craniectomy
Death
Wolf et al. [21]
22 y/o
Female
N/A
Shivering, fever,
and headaches
for two days, with
spontaneous
resolution
ChAdOx1
nCoV-19
(AstraZeneca)
Platelets=
75000/Ul
D-dimer= 2590
ng/ml
Anti-PF4
Superior sagittal sinus, left
side transverse sinus, sigmoid
sinus, and ascending cerebral
veins thrombosis.
Endovascular rheolysis,
2 x 1000 mg levetiracetam
(PO) daily for three months, 2
x 80 mg enoxaparin sodium
(SC) daily for ten days,
Recovered
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Day 4: New
frontally
accentuated
headaches
Day 7: A self-
limited
generalized
epileptic seizure
occurred.
antibodies were
positive
followed by direct oral
anticoagulation with 2 x 150
mg dabigatran PO daily for six
months.
Wolf et al. [21]
46 y/o
Female
N/A
Severe headaches
eight days after
the first dose
ChAdOx1
nCoV-19
(AstraZeneca)
Platelets=
60,000/ul
Anti-PF4
antibodies were
positive
Superior sagittal sinus, left-
hand transverse sinus,
sigmoid sinus thrombosis.
Endovascular rheolysis in two
separate sessions, 2 x 80mg
SC Enoxaparin for 2 days then
changed to 3 x 750mg
Danaparoid
Recovered
Wolf et al. [21]
36 y/o
Female
N/A
Severe headaches
seven days after
the first dose,
three days of
fever and
headache, acute
somnolence, and
right-hand
hemiparesis
ChAdOx1
nCoV-19
(AstraZeneca)
Platelets=
92000/ul
Anti-PF4
antibodies were
positive
Straight sinus thrombosis,
non-occlusive thrombus in the
superior sagittal sinus
2250 IU danaparoid SC,
endovascular rheolysis, 2 x 60
mg enoxaparin sodium SC
daily for one week, followed
by direct oral anticoagulation
with 2 x 150 mg dabigatran
PO daily for six months
Recovered
Bjørnstad-Tuveng
et al [19]
Female in
her 30s
An uncomplicated
birth 11 months prior
with 1500ml
bleeding, mild
preeclampsia treated
with labetalol 100
mg. For the past 3
months, she used
Duroferon 2 x 100
mg for iron
deficiency and
desloratadine 5 mg
for allergies.
Headache after 7
days of
vaccination. This
was followed by a
worsening
headache, slurred
speech, and
uncoordinated
walking and
movement.
ChAdOx1
nCoV-19
(AstraZeneca)
Platelets=
37 x 109/L
D-dimer
> 7.0 mg/L
Anti-PF4
antibodies were
positive
Postmortem examination
revealed fresh small thrombi
in the transverse sinus, frontal
lobe, and pulmonary artery.
1 g of tranexamic acid
intravenously, midazolam for
seizure
Death
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Table 1. A tabulation of the outcomes of literature review of VITT following SARS-CoV-2 vaccination
N/A: Not Available, OCP: Oral contraceptives, IVIG: Intravenous Immunoglobulins, ITP: Immune thrombocytopenia, PE: Pulmonary embolism, CVST:
Cerebral venous sinus thrombosis, IV: Intravenous, SC: Subcutaneous, PO: Per os LMWH: Low molecular weight heparin, DVT: Deep vein thrombosis
Tarawneh et al.
[48]
22 y/o male
N/A
Petechia and
gums bleeding 3
days post-
vaccination
Pfizer-
BioNTech
mRNA
Platelets= 2 x 109
N/A
Dexamethasone 40 mg daily
for 4 days, platelet
transfusion, and IVIG at 1 g/kg
for 2 days
Recovered
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Highlights
 The global vaccination program against COVID-19 has greatly reduced the number of deaths and
cases.
 This review evaluates all the currently available literature and highlights potential
pathophysiology, clinical approach to diagnose VITT and its management.
 The escalating incidence of thrombotic events and thrombocytopenia post-COVID-19
vaccination has raised concerns regarding the safety profile of available vaccines
 VITT has been acknowledged as a rare adverse effect of SARS-CoV-2 vaccination, and the
benefits of COVID-19 vaccines continue to markedly outweigh the rare ramifications.
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Annals of Medicine and Surgery
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The Guarantor is the one or more people who accept full responsibility for the work and/or the
conduct of the study, had access to the data, and controlled the decision to publish
Zohaib Yousaf (MBBS, MSc, FACP)
Department of Internal Medicine,
Hamad Medical Corporation, Doha, Qatar
Email: zohaib.yousaf@gmail.com
Irfan Ullah, MBBS
Kabir Medical College, Gandhara University,
Peshawar, Pakistan
Irfanullahecp2@gmail.com
+923340968239
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